PLAGL2 Regulates Wnt Signaling to Impede Differentiation in Neural Stem Cells and Gliomas

Zheng, Hongwu; Ying, Haoqiang; Wiedemeyer, Ruprecht; Yan, Haiyan; Quayle, Steven N.; Ivanova, Elena; Paik, Ji Hye; Zhang, Hailei; Xiao, Yonghong; Perry, Samuel R.; Hu, Jian; Vinjamoori, Anant; Gan, Boyi; Sahin, Ergün; Chheda, Milan G.; Brennan, Cameron; Wang, Y. Alan; Hahn, William C.; Chin, Lynda; DePinho, Ronald A.

doi:10.1016/j.ccr.2010.03.020

Cited by 233 publications

(254 citation statements)

References 70 publications

(111 reference statements)

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“…20 Furthermore, Wnt/b-catenin signaling is regulated by PLAGL2 and FoxM1 proto-oncogenes during gliomagenesis. 18,22 Here, we identified PY142 b-catenin as a nuclear b-catenin form that signals through transcriptional regulation in GBM. PY142 b-catenin is different from classical active b-catenin: PY142 b-catenin accumulates in the nucleus already in astrocytoma (grade II and III) samples and correlates with high levels of the migration marker Snail/Slug in tumor biopsies.…”

Section: Resultsmentioning

confidence: 99%

“…[10][11][12] Hepatocyte Growth Factor (HGF) and its receptor c-Met are both overexpressed in GBM, contributing to tumor growth invasion, angiogenesis and conferring a stem-like phenotype and poor prognosis. 10,[13][14][15][16] Although activating mutations of b-catenin have not been identified in GBM 17 , overexpression of b-catenin and other Wnt pathway components (including Fz 18 ) together with epigenetic regulation of Wnt inhibitors results in Wnt/ b-catenin activation in GBM. [19][20][21] Overexpression of the Forkhead box M1 (FoxM1) transcription factor represents a critical mechanism further contributing to b-catenin signaling in GBM.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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“…Primary mouse PM-NSCs and GSCs were isolated from the brain subventricular zone (SVZ) of E13.5 mouse embryos and mouse brain tumors with the indicated genotypes as previously described, respectively (17,18). PMNSCs and GSCs were maintained in stem cell media (SCM) (05702; StemCell) supplemented with 20 ng/mL EGF (E4127; Sigma) and 10 ng/mL basic FGF (F0291; Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults (4, 5), possesses both glioma stem cells (GSCs) (6-12) and more differentiated tumor cells, which manifest as significant morphological heterogeneity characterized by immature glial and neuronal features (4,(13)(14)(15). Current evidence has established that the GSC state is driven in part by WNT and Myc (16)(17)(18), which promote stemness yet allow for partial cellular differentiation capacity, a process thought to fuel cellular heterogeneity in GBM (13,15). In this study, we sought to answer whether loss of terminal differentiation capacity simply reflects acquisition of enhanced selfrenewal capability of GSCs or whether the genes that drive cells toward terminal differentiation are also actively neutralized through mutations/genomic alterations, and if so, whether such genetic events are essential in gliomagenesis.…”

mentioning

confidence: 99%

Neutralization of terminal differentiation in gliomagenesis

Yuan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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An immature state of cellular differentiation-characterized by stem cell-like tendencies and impaired differentiation-is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNAbinding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.oncogenomics | cancer stem cells

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“…Identification of molecular pathways essential for CSC self-renewal is critical for designing effective cancer therapeutics. The Wnt signaling pathway is an essential pathway that regulates non-neoplastic stem cells, including cell proliferation, differentiation and migration processes, which have been verified in various stem cells such as embryonic stem cells (9,10), neural progenitor cells (11,12), hematopoietic (13) and cardiovascular stem cells (14). The similarities between normal adult stem cells and CSCs suggest that the signaling pathways involved in somatic stem cell maintenance may also be involved in the regulation of CSCs.…”

Section: Introductionmentioning

confidence: 99%

The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer

Cai

Zhu

2012

Mol Med Report

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Abstract. Cancer stem cells (CSCs) possess the ability of self-renewal and tumor initiation. Targeting key signaling pathways that are active in CSC self-renewal is one approach to cancer therapy. Abnormal activation of the Wnt/β-catenin pathway has been described in a wide variety of human cancers and in CSCs; however, the role of this pathway in gastric CSCs has not been reported. In our study, we investigated whether the Wnt/β-catenin pathway plays an important role in gastric CSCs. First, we isolated cancer stem-like cells (CSLCs) from the human gastric cancer cell line MKN-45 using tumorsphere cultures. We tested whether tumorsphere cells were CSLCs using the following three criteria: i) We identified that the expression of the CSC marker CD44 was significantly greater in tumorsphere cells compared to adherent cells; ii) compared with adherent cells, the floating tumorsphere cells had greater self-renewing capacity; iii) in vivo xenograft studies showed that tumorsphere cells generate larger tumors than adherent cells at the same number. In addition, we studied the mechanism(s) by which the canonical Wnt signaling pathway acts in CSLCs. Western blotting and real-time PCR showed that the expression levels of β-catenin and c-myc, cyclin d1 and axin 2 were downregulated/upregulated with the inhibition/activation of the Wnt pathway. The pathway blocked by DKK-1 caused a higher reduction in the self-renewing capacity of MKN-45 tumorsphere cells and the pathway activated by lithium chloride improved the self-renewal of CSLCs. In conclusion, our data suggested that the Wnt/β-catenin pathway is essential for the self-renewal of CSLCs in human gastric cancer.

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PLAGL2 Regulates Wnt Signaling to Impede Differentiation in Neural Stem Cells and Gliomas

Cited by 233 publications

References 70 publications

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Neutralization of terminal differentiation in gliomagenesis

The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer

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